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Original Investigation | Psychiatry

Association of Use of Omega-3 Polyunsaturated Fatty Acids


With Changes in Severity of Anxiety Symptoms
A Systematic Review and Meta-analysis
Kuan-Pin Su, MD, PhD; Ping-Tao Tseng, MD; Pao-Yen Lin, MD, PhD; Ryo Okubo, MD, PhD; Tien-Yu Chen, MD; Yen-Wen Chen, MD; Yutaka J. Matsuoka, MD, PhD

Abstract Key Points


Question Is omega-3 polyunsaturated
IMPORTANCE No systematic review or meta-analysis has assessed the efficacy of omega-3
fatty acid treatment associated with an
polyunsaturated fatty acids (PUFAs) for anxiety.
improvement in anxiety symptoms?

OBJECTIVE To evaluate the association of anxiety symptoms with omega-3 PUFA treatment Findings In this systematic review and
compared with controls in varied populations. meta-analysis of 19 clinical trials
including 2240 participants from 11
DATA SOURCES PubMed, Embase, ProQuest, ScienceDirect, Cochrane Library, ClinicalKey, Web of countries, improvement in anxiety
Science, and ClinicalTrials.gov databases were searched up to March 4, 2018. symptoms was associated with omega-3
polyunsaturated fatty acid treatment
STUDY SELECTION A search was performed of clinical trials assessing the anxiolytic effect of compared with controls in both placebo-
omega-3 PUFAs in humans, in either placebo-controlled or non–placebo-controlled designs. Of 104 controlled and non–placebo-controlled
selected articles, 19 entered the final data extraction stage. trials. The anxiolytic effects of omega-3
polyunsaturated fatty acids were also
DATA EXTRACTION AND MEASURES Two authors independently extracted the data according to stronger in participants with clinical
a predetermined list of interests. A random-effects model meta-analysis was performed and this conditions than in subclinical
study was conducted based on Preferred Reporting Items for Systematic Reviews and Meta-analyses populations.
guidelines.
Meaning Omega-3 polyunsaturated
fatty acid treatment for anxiety might be
MAIN OUTCOMES AND MEASURES Changes in the severity of anxiety symptoms after omega-3
effective in clinical settings.
PUFA treatment.

RESULTS In total, 1203 participants with omega-3 PUFA treatment (mean age, 43.7 years; mean + Supplemental content
female proportion, 55.0%; mean omega-3 PUFA dosage, 1605.7 mg/d) and 1037 participants without Author affiliations and article information are
omega-3 PUFA treatment (mean age, 40.6 years; mean female proportion, 55.0%) showed an listed at the end of this article.

association between clinical anxiety symptoms among participants with omega-3 PUFA treatment
compared with control arms (Hedges g, 0.374; 95% CI, 0.081-0.666; P = .01). Subgroup analysis
showed that the association of treatment with reduced anxiety symptoms was significantly greater
in subgroups with specific clinical diagnoses than in subgroups without clinical conditions. The
anxiolytic effect of omega-3 PUFAs was significantly better than that of controls only in subgroups
with a higher dosage (at least 2000 mg/d) and not in subgroups with a lower dosage (<2000 mg/d).

CONCLUSIONS AND RELEVANCE This review indicates that omega-3 PUFAs might help to reduce
the symptoms of clinical anxiety. Further well-designed studies are needed in populations in whom
anxiety is the main symptom.

JAMA Network Open. 2018;1(5):e182327. doi:10.1001/jamanetworkopen.2018.2327

Open Access. This is an open access article distributed under the terms of the CC-BY License.

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JAMA Network Open | Psychiatry Association of Omega-3 Polyunsaturated Fatty Acids With Anxiety Symptom Severity

Introduction
Anxiety, the most commonly experienced psychiatric symptom, is a psychological state derived from
inappropriate or exaggerated fear leading to distress or impairment. The lifetime prevalence of any
anxiety disorder is reported to be approximately 1 in 3.1 Anxiety is often comorbid with depressive
disorders2 and is associated with lower health-related quality of life3 and increased risk of all-cause
mortality.4 Treatment options include psychological treatments, such as cognitive-behavioral
therapy and pharmacological treatments, mainly with selective serotonin reuptake inhibitors.5
Individuals with anxiety and related disorders tend to be more concerned about the potential
adverse effects of pharmacological treatments (eg, sedation or drug dependence) and may be
reluctant to engage in psychological treatments that can be time-consuming and costly, as well as
sometimes limited in availability.6 Thus, evidence-based and safer treatments are required, especially
for anxious patients with comorbid medical conditions.
Omega-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA), are essential nutrients that have potential preventive and therapeutic
effects on psychiatric disorders, such as anxiety and depression,7-15 as well as comorbid depression
and anxiety in physically ill patients,16-19 patients with coronary heart disease,20,21 and pregnant
women.22,23 Preclinical data support the effectiveness of omega-3 PUFAs as treatment for anxiety
disorders. Song et al24,25 found that an EPA-rich diet could reduce the development of anxiety-like
behaviors in rats as well as normalize dopamine levels in the ventral striatum. In addition, Yamada
et al26 showed that a high dietary omega-3 to omega-6 PUFA ratio reduced contextual fear behaviors
in mice and that these effects were abolished by a cannabinoid CB1 receptor antagonist.
A number of trials have found that omega-3 PUFAs might reduce anxiety under serious stressful
situations. Case-controlled studies have shown low peripheral omega-3 PUFA levels in patients with
anxiety disorders.27-31 A cohort study found that high serum EPA levels were associated with
protection against posttraumatic stress disorder.32 In studies of therapeutic interventions, while a
randomized clinical trial of adjunctive EPA treatment in patients with obsessive-compulsive disorder
revealed that EPA augmentation had no beneficial effect on symptoms of anxiety, depression, or
obsessive-compulsiveness,33 a randomized clinical trial involving participants with substance abuse
showed that EPA and DHA administration was accompanied by significant decreases in anger and
anxiety scores compared with placebo.34 In addition, a randomized clinical trial found that omega-3
PUFAs had additional effects on decreasing depressive and anxiety symptoms in patients with acute
myocardial infarction,35 and a randomized clinical trial demonstrated that omega-3 PUFAs could
reduce inflammation and anxiety among healthy young adults facing a stressful major examination.36
Despite the largely positive findings of these trials, the clinical application of the findings is
unfortunately limited by their small sample sizes.
We hypothesized that omega-3 PUFAs might have anxiolytic effects in patients with significant
anxiety- and fear-related symptoms. However, there have been no systematic reviews of this topic
to date. Thus, we examined the anxiolytic effects of omega-3 PUFAs in participants with elevated
anxiety symptoms in the results of clinical trials to determine the overall efficacy of omega-3 PUFAs
for anxiety symptoms irrespective of diagnosis.

Methods
This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-
analyses (PRISMA) reporting guidelines.37 The study protocol adhered to the requirements of the
institutional review board of Tri-Service General Hospital.

Literature Search and Screening


Two psychiatrists (P.-T.T. and T.-Y.C.) separately performed a systematic literature search of the
PubMed, Embase, ProQuest, ScienceDirect, Cochrane Library, ClinicalKey, Web of Science, and

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ClinicalTrials.gov databases to March 4, 2018. Because we presumed some clinical trials would use
investigating scales for some other mood symptoms but also contain symptoms of anxiety, we tried
to use some nonspecific medical subject heading terms to include those clinical trials. Therefore, we
used the following keywords: omega-3, eicosapentaenoic acid, EPA, DHA, or docosahexaenoic acid;
and anxiety, anxiety disorder, generalized anxiety disorder, agoraphobia, panic disorder, or
posttraumatic stress disorder. After removing duplicate studies, the same 2 authors screened the
search results according to the title and abstract to evaluate eligibility. List of potentially relevant
studies were generated for a full-text review. Any inconsistencies were discussed with a third author
to achieve final consensus. To expand the list of potentially eligible articles, we performed a manual
search of the reference lists of review articles in this area.12,38,39
Because of the preliminary state of knowledge on the effects of omega-3 PUFA treatment on
anxiety, we decided to include as many studies as possible and not to set further limitations on
specific characteristics, such as length of study, diagnosis, omega-3 PUFA dosage, omega-3 PUFA
preparation (EPA to DHA ratio), rated anxiety coding scale, or type of control. Therefore, we chose to
make the inclusion criteria as broad as possible to avoid missing any potentially eligible studies. The
inclusion criteria included clinical trials in humans (randomized or nonrandomized), studies
investigating the effects of omega-3 PUFA treatment on anxiety symptoms, and formal published
articles in peer-reviewed journals. The clinical trials could be placebo controlled or non–placebo
controlled. The target participants could include healthy volunteers, patients with psychiatric illness,
and patients with physical illnesses other than psychiatric illnesses. The exclusion criteria included
case reports or series, animal studies or review articles, and studies not investigating the effects of
omega-3 PUFA treatment on anxiety symptoms. We did not set any language limitation to increase
the number of eligible articles. Figure 1 shows the literature search and screening protocol.

Meta-analysis and Data Extraction and Input


Due to the anticipated heterogeneity, a random-effects meta-analysis was chosen rather than a
fixed-effects meta-analysis because random-effects modeling is more stringent and incorporates an
among-study variance in the calculations. The entire meta-analysis procedure was performed on the
platform of Comprehensive Meta-analysis statistical software, version 3 (Biostat). Under the
preliminary assumption that the scales for anxiety symptoms are heterogeneous among the
recruited studies, we chose Hedges g and 95% confidence intervals to combine the effect sizes, in
accordance with the manual of the Comprehensive Meta-analysis statistical software, version 3.
Regarding the interpretation of effect sizes, we defined Hedges g values 0 or higher as a better
association of treatment with reduced anxiety symptoms of omega-3 PUFAs than in controls. For
each analysis, a 2-tailed P value less than .05 was considered to indicate statistical significance. When
more than 1 anxiety scale was used in a study, we chose the one with the most informative data (ie,
mean and standard deviation [SD] before and after treatment). We entered the primary outcome
provided in the included articles or obtained from the original authors. As for the variance
imputation, we mainly chose the mean and SD before and after treatment. Later, we entered the
mean and SD and calculated the effect sizes based on the software option, standardized by post
score SD. In the case of studies with 2 active treatment arms, we merged the 2 active treatment arms
into 1 group. If these 2 active treatment arms belonged to different subgroups (ie, different PUFA
dosage subgroups), we kept them separate. Regarding the numbers of participants counted, we
chose intention-to-treat as our priority. If there were insufficient data in the intention to treat group
(ie, some studies only provided the changes in anxiety severity in those participants completing
trials), we chose instead the per-protocol numbers of participants.
The quality of the included clinical trials were assessed using the Jadad score,40 which was
designed to evaluate the risk of bias in interventional trials in 3 specific domains: randomization,
blindness, and cohort follow-up.
The primary outcome was analyzed by changes in anxiety symptoms in patients receiving
omega-3 PUFA treatment compared with those not receiving omega-3 PUFA treatment.

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Heterogeneity, Publication Bias, and Sensitivity Testing


Heterogeneity was examined using the Q statistic and the corresponding P values,41 and the I2
statistic was used to evaluate the proportion of variation resulting from among-study differences.
Any possible publication bias was detected with both funnel plots and Egger regression in the main
part of the meta-analysis.42 By using Duval and Tweedie’s trim-and-fill test, we adjusted the effect
sizes for potential publication bias if there was evidence of publication bias detected by this test in
the Comprehensive Meta-analysis statistical software, version 3.43 To investigate the potential
confounding effects of any outliers within the recruited studies, sensitivity testing was conducted
with the 1-study removal method to detect the potential outliers.44

Metaregression and Subgroup Meta-analysis


To exclude the possible confounding effects of clinical variables on the Hedges g, metaregression
analysis was conducted with an unrestricted maximum likelihood random-effects model of single
variables when there were more than 10 data sets available. Specifically, the clinical variables of
interest included mean age, female proportion, sample size, mean body mass index, daily omega-3
PUFA dosage, EPA to DHA ratio, treatment duration, dropout rate, and others. In addition, a
subgroup meta-analysis was conducted to investigate potential sources of heterogeneity,
specifically, a further subgroup meta-analysis focused on those trials that were placebo controlled or
non–placebo controlled. To more clearly uncover the differences in the meta-analysis results among
the recruited studies, a further subgroup meta-analysis was performed according to the presence of
a specific clinical diagnosis or no specific clinical condition, mean omega-3 PUFA daily dosage, and

Figure 1. Flowchart of the Selection Strategy and Inclusion and Exclusion Criteria for This Meta-analysis

3584 Records identified through 4 Additional records identified through


database searching other sources

3588 Records identified

1447 Excluded duplicated records

2141 Records after duplicates removed

2037 Excluded by title and abstract

104 Full-text articles assessed for


eligibility

85 Excluded articles
6 Not human clinical trials
2 Case report
7 Review article
2 Meta-analysis
15 Lack of adequate control
3 Duplicated database from
other studies
38 Not related to treatment
effect of omega-3 on anxiety
2 Protocol but not result of
study
3 Did not simply treat with PUFAs
1 Database study but not
clinical trial
6 No detailed information after
request of raw data

19 Studies included in current


meta-analysis

16 Compared with placebo


3 Do not use placebo
PUFAs indicates polyunsaturated fatty acids.

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mean age. In addition, in a previous study, the EPA percentage (ie, ⱖ60%) in the PUFA regimens had
different effects on depression treatment.9 Therefore, we also arranged the subgroup meta-
analysis based on the EPA percentage. Furthermore, we arranged subgroup meta-analysis
procedures only when there were at least 3 data sets included.45 To investigate the potentially
different estimated effect sizes between subgroups, we performed an interaction test and calculated
the corresponding P values.46

Results
Characteristics of the Included Studies
After the initial screening process, a total of 104 articles were considered for full-text review (Figure 1;
eFigure 1 in the Supplement); 85 were excluded according to the exclusion criteria (eAppendix in the
Supplement), leaving 19 articles for analysis in this study (Table).33-36,47-61
In the 19 recruited studies,33-36,47-61 there were a total of 1203 participants with omega-3 PUFA
treatment (mean age, 43.7 years; mean female proportion, 55.0%; mean omega-3 PUFA dosage,
1605.7 mg/d) and 1037 participants without omega-3 PUFA treatment (mean age, 40.6 years; mean
female proportion, 55.0%).
Various scales were used in these studies to evaluate the target outcome of anxiety symptoms:
the Yale-Brown Obsessive-Compulsive Scale, Profile of Mood States, State-Trait Anxiety Inventory,
Hamilton Anxiety Rating Scale, Generalized Anxiety Disorder questionnaire, Depression, Anxiety, and
Stress Scales, Clinician-Administered Posttraumatic Stress Disorder Scale, Beck Anxiety Inventory,
visual analog scale of anxiety, Impact of Event Scale–Revised, Conners score anxiety subscale,
Neuropsychiatric Inventory, test anxiety severity, Hospital Anxiety and Depression Scale anxiety
subscale, and Child Behavior Checklist anxiety subscale. The psychiatric and physical health
conditions of the recruited participants also varied widely: general population without specific clinical
conditions,36,47,51,55,60 participants with acute myocardial infarction,35 borderline personality
disorder,2 mild to severe depression,59 obsessive-compulsive disorder,33 severe accidental injury,49
participants who were traumatized by disaster,54 participants with substance abuse disorder,34
women with premenstrual syndrome,56 children with attention-deficit/hyperactivity disorder,48,53
Alzheimer disease,58 generally healthy undergraduate college students but with test anxiety,61
Parkinson disease,52 and participants with Tourette syndrome.57 Sixteen studies compared the effect
of omega-3 PUFA treatment with that of the placebo33,34,36,47-49,51-53,55-61; the other 3 studies were
non–placebo controlled trials.35,50,54 The mean (SD) Jadad score of the recruited studies was 3.8 (1.0)
(eTable in the Supplement).

Meta-analysis of Changes in Anxiety Symptoms in Patients Receiving


and Not Receiving Omega-3 PUFA Treatment
In total, 19 articles with 19 data sets revealed the main results of the meta-analysis, namely that there
was a significantly better association of treatment with reduced anxiety symptoms in patients
receiving omega-3 PUFA treatment than in those not receiving it (k, 19; Hedges g, 0.374; 95% CI,
0.081-0.666; P = .01; Figure 2), with significant heterogeneity (Cochran Q, 178.820; df, 18; I2,
89.934%; P < .001) but no significant publication bias via Egger regression (t, 1.736; df, 17; P = .10) or
inspection of the funnel plot (eFigure 2 in the Supplement). According to the trim-and-fill test, there
was no need for adjustment for publication bias. The meta-analysis results remained significant after
removal of any one of the included studies, which indicated that the significant results are not owing
to any single study.
There was no significant association between the Hedges g and mean age (k, 17; P = .51), female
proportion (k, 18; P = .32), mean omega-3 PUFA dosage (k, 19; P = .307), EPA to DHA ratio (k, 17;
P = .86), dropout rate in the omega-3 PUFA group (k, 18; P = .71), duration of omega-3 PUFA
treatment (k, 19; P = .14), Jadad score of randomization (k, 19; P = .10), Jadad score of blindness (k,
19; P = .57), or total Jadad score (k, 19; P = .18).

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Table. Characteristics of Recruited Studies
Treatment
Omega-3 Dropout Rate, Duration,
Source Diagnosis Comparison Participants, No. Anxiety Scale Age, Mean (SD), y Female, No. (%) Dosage, mg/d No./Total No. wk Country
Watanabe et al,47 2018 Junior nurses work in Omega-3 PUFA 40 HADS-A 29.6 (9.1) 40 (100.0) 1800.0 0/40 13 Japan
hospital Placebo 40 30.5 (7.8) 40 (100.0) 3/40
Cornu et al,48 2018 Children with ADHD Omega-3 PUFA 80 Conners 10.2 (2.8) 19 (23.7) 600.0 3/80 12 France
Placebo 82 9.7 (2.5) 16 (19.5) 1/82

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Matsuoka et al,49 2015 Severe accidental injury Omega-3 PUFA 53 CAPS 38.1 (13.5) 9 (17.0) 2100.0 8/53 12 Japan
Placebo 57 40.9 (17.3) 11 (19.3) 6/57
Bellino et al,50 2014 Borderline personality Omega-3 PUFA + valproate 18 HAM-A 25.2 (6.4) 26 (76.5) 2000.0 5/23 12 Italy
disorders Control + valproate 16 4/20
Cohen et al,51 2014 Generally healthy Omega-3 PUFA 177 GAD-7 54.7 (3.7) 177 (100.0) 1800.0 4/177 12 United States
JAMA Network Open | Psychiatry

participants Placebo 178 178 (100.0) 5/178


Pomponi et al,52 2014 Parkinson disease Omega-3 PUFA 12 HAM-A 64.0 (4.9) 5 (41.7) 2000.0 0/12 24 Italy
Placebo 12 64.0 (9.8) 6 (50.0) 0/12
Widenhorn-Müller Children with ADHD Omega-3 PUFA 46 CBCL-A 8.9 (1.5) 11 (23.9) 720.0 7/55 16 Germany
et al,53 2014 Placebo 49 8.9 (1.2) 10 (20.4) 6/55
Haberka et al,35 2013 AMI Omega-3 PUFA + AMI 26 STAI 56.4 3 (11.5) 1000.0 0/26 4 Poland
treatment 26 59.6 (6.0) 4 (15.4) 0/26
Control + AMI treatment
Nishi et al,54 2013 Disaster-related trauma Omega-3 PUFA + education 86 IES-R 37.9 (7.4) 24 (27.9) 2240.0 0/86 12.6 Japan
Education 86 37.4 (7.4) 23 (26.7) 1/86
Sauder et al,55 2013 Healthy, nonsmoking men Omega-3 PUFA (3.4 g/d) 26 STAI-state 44.0 3 (11.5) 3400.0 0/26 8 United States
and postmenopausal Omega-3 PUFA (0.85 g/d) 26 850.0 0/26
women with moderate Placebo 26 0/26
hypertriglyceridemia

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Sohrabi et al,56 2013 Women with premenstrual Omega-3 PUFA 63 VASA 31.2 (6.5) 63 (100.0) 1000.0 7/70 12 Iran
syndrome Placebo 61 31.6 (8.4) 61 (100.0) 8/69
Gabbay et al,57 2012 Tourette syndrome Omega-3 PUFA 17 C-YBOCS 11.9 (3.6) 3 (17.6) 4074.0 3/17 20 United States
Placebo 16 10.6 (2.3) 3 (18.8) 5/16
Kiecolt-Glaser et al,36 Generally healthy Omega-3 PUFA 34 BAI 23.9 (2.0) 16 (47.1) 2496.0 0/34 12 United States
2011 participants Placebo 34 23.4 (1.7) 14 (41.2) 0/34
Buydens-Branchey Substance abuse Omega-3 PUFA 11 POMS NA 0 3000.0 0/11 12 United States
et al,34 2008 Placebo 11 0 0/11
Freund-Levi et al,58 Alzheimer disease Omega-3 PUFA 89 NPI 72.6 (9.0) 51 (57.3) 2320.0 12/103 24 Sweden
2008 Placebo 85 72.9 (8.6) 39 (45.9) 14/101
Rogers et al,59 2008 Mild to severe depression Omega-3 PUFA 109 DASS 38.0 (13.5) 85 (78.0) 2369.5 13/109 12 United
Placebo 109 38.2 (13.7) 83 (76.1) 15/109 Kingdom
van de Rest et al,60 Elderly volunteers Omega-3 PUFA (1.8 g/d) 96 HADS-A 69.9 (3.4) 43 (44.8) 1800.0 0/96 26 Netherlands
2008 Omega-3 PUFA (0.4 g/d) 100 69.5 (3.2) 45 (45.0) 400.0 0/100
Placebo 106 70.1 (3.7) 47 (44.3) 3/106
Yehuda et al,61 2005 Undergraduate college Omega-3 PUFA 88 TAS NA NA 225.0 0/88 3 Israel
students with test anxiety Placebo 38 0/38
Fux et al,33 2004 Obsessive-compulsive Omega-3 PUFA 6 YBOCS 33.5 (5) 8 (72.7) 2000.0 1/11 6 Israel
disorder Placebo 5

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; AMI, acute myocardial infarction; BAI, Beck anxiety subscale; HAM-A, Hamilton anxiety rating scale; IES-R, impact of event scale-revised; NA, not available; NPI,
index; CAPS, clinician-administered posttraumatic stress disorder scale; CBCL-A, Child Behavior Checklist anxiety Neuropsychiatric Inventory; POMS, profiles of mood states; PUFA, polyunsaturated fatty acid; STAI, state-trait
subscale; C-YBOCS, children’s Yale-Brown obsessive-compulsive scale; DASS, depression, anxiety, and stress anxiety inventory; TAS, test anxiety severity; VASA, visual analog scale of anxiety; YBOCS, Yale-Brown obsessive-
scales; GAD-7, generalized anxiety disorder questionnaire; HADS-A, Hospital Anxiety and Depression Scale anxiety compulsive scale.

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Subgroup Meta-analysis When Focusing on Placebo-Controlled Trials


or Non–Placebo-Controlled Trials
Among the 16 studies comparing the effect of omega-3 PUFA treatment with that of the
placebo,33,34,36,47-49,51-53,55-61 the main results revealed a significantly greater association of
treatment with reduced anxiety symptoms in patients receiving omega-3 PUFA treatment than in
those not receiving it (k, 16; Hedges g, 0.372; 95% CI, 0.032-0.712; P = .03; eFigure 3 in the
Supplement). The meta-analysis of the subgroup focusing on non–placebo-controlled trials also
showed a significantly greater association of treatment with reduced anxiety symptoms in patients
receiving omega-3 PUFA treatment than in those not receiving it (k, 3; Hedges g, 0.399; 95% CI,
0.154-0.643; P = .001).35,50,54

Subgroup Meta-analysis When Focusing on Trials Recruiting Participants


Without Specific Clinical Conditions or Trials Recruiting Participants
With Specific Clinical Diagnoses
Five studies with 7 data sets recruited participants without specific clinical conditions.36,47,51,55,60 The
main results revealed that there was no significant difference in the association of treatment with
reduced anxiety symptoms between patients receiving omega-3 PUFA treatment and those not
receiving it (k, 5; Hedges g, –0.008; 95% CI, –0.266 to 0.250; P = .95) (Figure 3A). Fourteen studies
with 14 data sets recruited participants with specific clinical diagnoses.33-35,48-50,52-54,56-59,61 The
main results revealed a significantly greater association of treatment with reduced anxiety symptoms
in patients receiving omega-3 PUFA treatment than in those not receiving it (k, 14; Hedges g, 0.512;
95% CI, 0.119-0.906; P = .01) (Figure 3A). Furthermore, according to the interaction test, the
association of omega-3 PUFA treatment with reduced anxiety symptoms was significantly stronger
in subgroups with specific clinical diagnoses than in subgroups without specific clinical conditions
(P = .03).

Figure 2. Meta-Analysis Forest Plot of the Association of Treatment With Reduced Anxiety Symptoms in Patients Receiving and Not Receiving omega-3 PUFAs
Participants, No. Worse effect Better effect Relative
Source Omega-3 Control Hedges g (95% CI) P Value by omega-3 PUFAs by omega-3 PUFAs Weight, %
Sauder et al,55 2013 52 26 –0.290 (–0.759 to 0.178) .22 5.40
van de Rest et al,60 2008 196 106 –0.214 (–0.450 to 0.023) .08 6.03
Freund-Levi et al,58 2008 36 24 –0.149 (–0.659 to 0.362) .57 5.27
Cohen et al,51 2014 177 178 –0.139 (–0.347 to 0.069) .19 6.08
Matsuoka et al,49 2015 53 57 –0.107 (–0.479 to 0.264) .57 5.70
Cornu et al,48 2018 79 81 –0.077 (–0.385 to 0.232) .63 5.87
Widenhorn-MÜller et al,53 2014 46 49 0.081 (–0.318 to 0.481) .69 5.62
Fux et al,33 2004 6 5 0.165 (–0.922 to 1.252) .77 3.36
Bellino et al,50 2014 18 16 0.172 (–0.487 to 0.831) .61 4.76
Rogers et al,59 2008 109 109 0.200 (–0.065 to 0.465) .14 5.97
Watanabe et al,47 2018 40 40 0.217 (–0.219 to 0.652) .33 5.51
Gabbay et al,57 2012 17 16 0.306 (–0.364 to 0.976) .37 4.72
Nishi et al,54 2013 86 86 0.382 (0.082 to 0.683) .01 5.89
Pomponi et al,52 2014 12 12 0.477 (–0.308 to 1.261) .23 4.32
Kiecolt-Glaser et al,36 2011 34 34 0.607 (0.126 to 1.088) .01 5.36
Haberka et al,35 2013 26 26 0.610 (0.062 to 1.158) .03 5.14
Buydens-Branchey et al,34 2008 11 11 1.010 (0.153 to 1.868) .02 4.07
Yehuda et al,61 2005 88 38 1.650 (1.220 to 2.079) <.001 5.53
Sohrabi et al,56 2013 63 61 2.459 (1.994 to 2.923) <.001 5.42
Overall 0.374 (0.081 to 0.666) .01 100.00

–4 –2 0 2 4
Hedges g (95% CI)

There was a significant improvement in anxiety symptoms in patients receiving omega-3 PUFAs than in those not receiving omega-3 PUFAs (k, 19; Hedges g, 0.374; 95% CI, 0.081-
0.666; P = .01).

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Figure 3. Forest Plot of Subgroup Meta-analysis

A An underlying specific clinical diagnosis or not

Participants, No. Worse effect Better effect Relative


Source Omega-3 Control Hedges g (95% CI) P Value by omega-3 PUFAs by omega-3 PUFAs Weight, %
No specific clinical conditions
Sauder et al,55 2013 52 26 –0.290 (–0.759 to 0.178) .22 15.68
van de Rest et al,60 2008 196 106 –0.214 (–0.450 to 0.023) .08 25.46
Cohen et al,51 2014 177 178 –0.139 (–0.347 to 0.069) .19 26.75
Watanabe et al,47 2018 40 40 0.217 (–0.219 to 0.652) .33 16.86
Kiecolt-Glaser et al,36 2011 34 34 0.607 (0.126 to 1.088) .01 15.25
Overall –0.008 (–0.266 to 0.250) .95 100.00
Specific clinical diagnoses
Freund-Levi et al,58 2008 36 24 –0.149 (–0.659 to 0.362) .57 7.33
Matsuoka et al,49 2015 53 57 –0.107 (–0.479 to 0.264) .57 7.78
Cornu et al,48 2018 79 81 –0.077 (–0.385 to 0.232) .63 7.96
Widenhorn-MÜller et al,53 2014 46 49 0.081 (–0.318 to 0.481) .69 7.70
Fux et al,47 2004 6 5 0.165 (–0.922 to 1.252) .77 5.11
Bellino et al,50 2014 18 16 0.172 (–0.487 to 0.831) .61 6.78
Rogers et al,59 2008 109 109 0.200 (–0.065 to 0.465) .14 8.06
Gabbay et al,57 2012 17 16 0.306 (–0.364 to 0.976) .37 6.73
Nishi et al,54 2013 86 86 0.382 (0.082 to 0.683) .01 7.98
Pomponi et al,52 2014 12 12 0.477 (–0.308 to 1.261) .23 6.28
Haberka et al,35 2013 26 26 0.610 (0.062 to 1.158) .03 7.20
Buydens-Branchey et al,34 2008 11 11 1.010 (0.153 to 1.868) .02 5.99
Yehuda et al,61 2005 88 38 1.650 (1.220 to 2.079) <.001 7.61
Sohrabi et al,56 2013 63 61 2.459 (1.994 to 2.923) <.001 7.49
Overall 0.512 (0.119 to 0.906) .01 100.00

–4 –2 0 2 4
Hedges g (95% CI)

B Different mean omega-3 PUFA dosages

Participants, No. Worse effect Better effect Relative


Source Omega-3 Control Hedges g (95% CI) P Value by omega-3 PUFAs by omega-3 PUFAs Weight, %
Dosage <2000 mg/d
Sauder et al,55 2013 26 26 –0.386 (–0.927 to 0.154) .16 10.60
van de Rest et al,60 2008 196 106 –0.214 (–0.450 to 0.023) .08 11.62
Cohen et al,51 2014 177 178 –0.139 (–0.347 to 0.069) .19 11.66
Cornu et al,48 2018 79 81 –0.077 (–0.385 to 0.232) .63 11.43
Widenhorn-MÜller et al,53 2014 46 49 0.081 (–0.318 to 0.481) .69 11.15
Watanabe et al,47 2018 40 40 0.217 (–0.219 to 0.652) .33 11.02
Haberka et al,35 2013 26 26 0.610 (0.062 to 1.158) .03 10.56
Yehuda et al,61 2005 88 38 1.650 (1.220 to 2.079) <.001 11.04
Sohrabi et al,56 2013 63 61 2.459 (1.994 to 2.923) <.001 10. 91
Overall 0.457 (–0.077 to 0.991) .09 100.00
Dosage ≥2000, mg/d
Sauder et al,55 2013 26 26 –0.193 (–0.730 to 0.344) .48 8.42
Freund-Levi et al,58 2008 36 24 –0.149 (–0.659 to 0.362) .57 9.05
Matsuoka et al,49 2015 53 57 –0.107 (–0.479 to 0.264) .57 13.62
Fux et al,33 2004 6 5 0.165 (–0.922 to 1.252) .77 2.57
Bellino et al,50 2014 18 16 0.172 (–0.467 to 0.831) .61 6.14
Rogers et al,49 2008 109 109 0.200 (–0.065 to 0.465) .14 18.89
Gabbay et al,57 2012 17 16 0.306 (–0.364 to 0.976) .37 5.97
Nishi et al,54 2013 86 86 0.382 (0.082 to 0.683) .01 16.96
Pomponi et al,52 2014 12 12 0.477 (–0.308 to 1.261) .23 4.60
Kiecolt-Glaser et al,36 2011 34 34 0.607 (0.126 to 1.088) .01 9.84
Buydens-Branchey et al,34 2008 11 11 1.010 (0.153 to 1.868) .02 3.94
Overall 0.213 (0.031 to 0.395) .02 100.00
–4 –2 0 2 4
Hedges g (95% CI)

A, Subgroup meta-analysis of the anxiolytic effect of omega-3 polyunsaturated fatty stronger in subgroups with specific clinical diagnoses than in subgroups without specific
acids (PUFAs) based on an underlying specific clinical diagnosis or not. The anxiolytic clinical conditions (P = .03). B, Subgroup meta-analysis of the anxiolytic effect of
effect of omega-3 PUFAs was not significant in the subgroup of participants without omega-3 PUFAs based on different mean omega-3 PUFA dosages. The anxiolytic effect
specific clinical conditions (k, 5; Hedges g, –0.008; 95% CI, –0.266 to 0.250; P = .95) but of omega-3 PUFAs was not significant in subgroups of mean omega-3 PUFA dosages less
was significant in the subgroup of participants with specific clinical diagnoses (k, 14; than 2000 mg/d (k, 9; Hedges g, 0.457; 95% CI, –0.077 to 0.991; P = .09) but was
Hedges g, 0.512; 95% CI, 0.119-0.906; P = .01). Furthermore, the association of significant in the subgroup of mean omega-3 PUFA dosage of at least 2000 mg/d (k, 11;
treatment with reduced anxiety symptoms of omega-3 PUFAs were significantly Hedges g, 0.213; 95% CI, 0.031-0.395; P = .02).

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Subgroup Meta-analysis When Focusing on Trials With Omega-3 PUFA Dosages


of Less Than 2000 mg/d or at Least 2000 mg/d
Nine studies with 10 data sets used omega-3 PUFA dosages of less than 2000
mg/d.35,47,48,51,53,55,56,60,61 The main results revealed that there was no significant difference in the
association of treatment with reduced anxiety symptoms between patients receiving omega-3 PUFA
treatment and those not receiving it (k, 9; Hedges g, 0.457; 95% CI, –0.077 to 0.991; P = .09)
(Figure 3B). Ten studies with 10 data sets used omega-3 PUFA dosages of at least 2000
mg/d.33,34,36,49,50,52,54,55,57-59 The main results revealed a significantly greater association of
treatment with reduced anxiety symptoms in patients receiving omega-3 PUFA treatment than in
those not receiving it (k, 11; Hedges g, 0.213; 95% CI, 0.031-0.395; P = .02) (Figure 3B). Furthermore,
there was no significantly different estimated effect sizes between these 2 subgroups by the
interaction test (P = .40).

Subgroup Meta-analysis of Trials With an EPA Percentage Less Than 60%


or an EPA Percentage of at Least 60%
There was a significantly greater association of treatment with reduced anxiety symptoms in
participants receiving omega-3 PUFAs than in those not receiving omega-3 PUFAs in the subgroup
with an EPA percentage less than 60% (k, 11; Hedges g, 0.485; 95% CI, 0.017-0.954; P = .04;
Figure 4)35,49,52,54-61 but no significant difference in the association of treatment with reduced
anxiety symptoms between participants receiving omega-3 PUFAs and those not receiving omega-3
PUFAs in the subgroup with an EPA percentage of at least 60% (k, 9; Hedges g, 0.092; 95% CI,
–0.102 to 0.285; P = .35) (Figure 4).33,34,36,47,48,50,51,53,60 There were no significantly different
estimated effect sizes between these 2 subgroups by the interaction test (P = .13).

Figure 4. Subgroup Meta-analysis With Different Eicosapentaenoic Acid (EPA) Percentages

Participants, No. Hedges g Worse effect Better effect Relative


Source Omega-3 Control (95% CI) P Value by omega-3 PUFAs by omega-3 PUFAs Weight, %
EPA percentage <60%
Sauder et al,55 2013 52 26 –0.290 (–0.759 to 0.178) .22 9.12
Van de Rest et al,60 2008 100 106 –0.157 (–0.430 to 0.116) .26 9.71
Freund-Levi et al,58 2008 36 24 –0.149 (–0.659 to 0.362) .57 8.97
Matsuoka et al,49 2015 53 57 –0.107 (–0.479 to 0.264) .57 9.44
Rogers et al,59 2008 109 109 0.200 (–0.065 to 0.465) .14 9.73
Gabbay et al,57 2012 17 16 0.306 (–0.364 to 0.976) .37 8.33
Nishi et al,54 2013 86 86 0.382 (0.082 to 0.683) .01 9.64
Pomponi et al,52 2014 12 12 0.477 (–0.308 to 1.261) .23 7.84
Haberka et al,35 2013 26 26 0.610 (0.062 to 1.158) .03 8.83
Yehuda et al,61 2005 86 38 1.650 (1.220 to 2.079) <.001 9.26
Sohrabi et al,56 2013 63 61 2.459 (1.994 to 2.923) <.001 9.14
Overall 0.485 (0.017 to 0.954) .04 100.00
EPA percentage ≥60%
Cohen et al,51 2014 177 178 –0.139 (–0.347to 0.069) .19 20.05
Van de Rest et al,60 2008 96 106 –0.131 (–0.406 to 0.144) .35 17.07
Cornu et al,48 2018 79 81 –0.077 (–0.385 to 0.232) .63 15.69
Widenhorn-MÜller et al,53 2014 46 49 0.081 (–0.318 to 0.481) .69 12.36
Fux et al,33 2004 6 5 0.165 (–0.922 to 1.252) .77 2.83
Bellino et al,50 2014 18 16 0.172 (–0.487 to 0.831) .61 6.49
Watanabe et al,47 2018 40 40 0.217 (–0.219 to 0.652) .33 11.25
Kiecolt-Glaser et al,36 2011 34 34 0.607 (0.126 to 1.088) .01 10.00
Buydens-Branchey et al,34 2008 11 11 1.010 (0.153 to 1.868) .02 4.26
Overall 0.092 (–0.102 to 0.285) .35 100.00

–4 –2 0 2 4
Hedges g (95% CI)

Subgroup meta-analysis of the anxiolytic effects of omega-3 polyunsaturated fatty acids g = 0.485; 95% CI, 0.017 to 0.954; P = .04) but not significant in the subgroups with an
(PUFAs) based on different EPA percentages. The anxiolytic effects of omega-3 PUFAs EPA percentage of at least 60% (k, 9; Hedges g, 0.092; 95% CI, –0.102 to
were significant in the subgroup with an EPA percentage less than 60% (k, 11; Hedges 0.285; P = .35).

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Other Subgroup Meta-analyses of Changes in Anxiety Symptoms in Patients


Receiving and Not Receiving Omega-3 PUFA Treatment
In addition, there was no significant difference in the association of treatment with reduced anxiety
symptoms between participants receiving omega-3 PUFAs and those not receiving omega-3 PUFAs
in the adolescent subgroup (aged <18 years) (k, 3; Hedges g, 0.020; 95% CI, –0.209 to 0.250;
P = .86),48,53,57 in the adult subgroup (aged ⱖ18 years but <60 years) (k, 11; Hedges g, 0.388; 95%
CI, –0.012 to 0.788; P = .06),33,35,36,47,49-51,54-56,59 or in the elderly subgroup (aged ⱖ60 years) (k, 3;
Hedges g, –0.112; 95% CI, –0.406 to 0.181; P = .45).52,58,60 These insignificant results might be due
to the smaller sample sizes in each subgroup.

Discussion
To our knowledge, this is the first systematic review and meta-analysis to examine the anxiolytic
effects of omega-3 PUFAs in individuals with anxiety symptoms. The overall findings revealed
modest anxiolytic effects of omega-3 PUFAs in individuals with various neuropsychiatric or major
physical illnesses. Although participants and diagnoses were heterogeneous, the main finding of this
meta-analysis was that omega-3 PUFAs were associated with significant reduction in anxiety
symptoms compared with controls; this effect persisted vs placebo controls. Furthermore, the
association of treatment with reduced anxiety symptoms of omega-3 PUFA were significantly higher
in subgroups with specific clinical diagnoses than in subgroups without clinical conditions.
Interestingly, the results are also consistent with our recent findings that somatic anxiety is
associated with omega-3 PUFA deficits and the genetic risks of PUFA metabolic enzyme cytosolic
phospholipase A2 in major depressive disorder62,63 and interferon α–induced neuropsychiatric
syndrome.63,64 Brain membranes contain a high proportion of omega-3 PUFAs and their derivatives
and most animal and human studies suggest that a lack of omega-3 PUFAs in the brain might induce
various behavioral and neuropsychiatric disorders,16,65-70 including anxiety-related
behaviors.12,18,19,32,49,71 Emerging evidence suggests that omega-3 PUFAs interfere with and possibly
control several neurobiological processes, such as neurotransmitter systems, neuroplasticity, and
inflammation,12,72 which is postulated to be the mechanism underlying anxiety and depression.
In our analysis, most of the included studies showed a positive Hedges g toward a beneficial
effect of omega-3 PUFAs in anxiety reduction, although not all findings were statistically significant.
However, after merging of these effect sizes from all of the included studies, the main result showed
significant findings in our meta-analysis. Despite the significant heterogeneity, no significant
publication bias was found among these 19 studies.
To evaluate the potential placebo effect, we made further subgrouping analyses. In the
subgroups of studies using placebo controls, the omega-3 PUFAs still revealed a consistent positive
anxiolytic association with anxiety symptoms. These phenomena meant that the anxiolytic effect of
omega-3 PUFAs is probably not entirely owing to the placebo effect.
Further, according to subgroup results based on the presence of specific clinical diagnoses or
not, the association of omega-3 PUFA treatment with reduced anxiety symptoms was significantly
higher in subgroups with specific clinical diagnoses than in subgroups without clinical conditions.
Among 6 studies included in a meta-analysis of the effect of omega-3 PUFAs on depressive
symptoms, the analysis showed a nearly null effect of omega-3 PUFAs on depressive symptoms in
healthy participants.73 Although the reason for the null effect of omega-3 PUFAs on anxiety and
depressive symptoms remains unclear, certain pathophysiological conditions might be required for
omega-3 PUFAs to exert an association of treatment with reduced anxiety symptoms.
Participants treated with a daily dose of 2000 mg or more of omega-3 PUFAs showed a
significantly greater association of treatment with reduced anxiety symptoms. In addition,
participants receiving supplements containing less than 60% EPA showed a significant association,
but not those receiving supplements containing 60% or more EPA. The depression literature
supports the clinical benefits of EPA-enriched formulations (ⱖ60% or ⱖ50%) compared with

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placebo for the treatment of clinical depression.9,13,73-75 This opposite effect of EPA-enriched
formations on anxiety and depression is intriguing and possibly linked to a distinct underlying
mechanism of omega-3 PUFAs. Exploration of the effects of omega-3 PUFAs on anxiety symptoms is
just beginning and studies assessing the dose response anxiolytic effects of omega-3 PUFAs have
not yet been performed. Further phase 2 trials of anxiety symptoms among participants with
neuropsychiatric illness or physical illness should aim to determine the optimal dose.
Although there was significant heterogeneity among the included studies (Cochran Q, 178.820;
df, 18; I2, 89.934%; P < .001), the sensitivity test suggested that the main significant results of the
meta-analysis would not change after removal of any of the included studies. However, through
direct inspection of the forest plot, we detected the potential influence of some outliers, such as the
studies by Sohrabi et al56 and Yehuda et al.61 These 2 studies evaluated anxiety symptoms with a
visual analog scale of anxiety and test anxiety severity, which are seldom used in psychiatric research
and lack a definite report to prove their equivalent sensitivity and specificity to some other
frequently used anxiety rating scales, such as depression, anxiety, and stress scales or the Hamilton
anxiety rating scale. Therefore, these studies might have affected the interpretation of the current
meta-analysis.
Finally, to investigate the potential confounding effects of some clinical variables, we tried to
conduct further exploratory subgroup analyses based on age. However, there were no significant
findings from these subgroups. These results might be due to the smaller sample sizes after
subgrouping.

Limitations
This article had several limitations and the findings need to be considered with caution. First, our
participant population is too heterogeneous because of our broad inclusion criteria, which might be
true if considering current Diagnostic and Statistical Manual of Mental Disorders or International
Classification of Diseases diagnostic systems. However, the novel Research Domain Criteria consider
anxiety to be one of the major domains in Negative Valence Systems. Trials should be conducted in
populations in which anxiety is the main symptom irrespective of the presence or absence of
diagnosis of anxiety disorder. Second, because of the limited number of recruited studies and their
modest sample sizes, the results should not be extrapolated without careful consideration. Third, the
significant heterogeneity among the included studies (Cochran Q, 178.820; df, 18; I2, 89.934%;
P < .001) with potential influence by some outlier studies, such as the studies by Sohrabi et al56 and
Yehuda et al,61 would be another major concern. Therefore, clinicians should pay attention to this
aspect when applying the results of the current meta-analysis to clinical practice, particularly when
considering the subgroups of these 2 studies (ie, subgroups with specific clinical diagnoses, with
<2000 mg/d, with EPA <60%, and with placebo-controlled trials).

Conclusions
This systematic review and meta-analysis of clinical trials conducted on participants with clinical
anxiety symptoms provides the first meta-analytic evidence, to our knowledge, that omega-3 PUFA
treatment may be associated with anxiety reduction, which might not only be due to a potential
placebo effect, but also from some associations of treatment with reduced anxiety symptoms. The
beneficial anxiolytic effects of omega-3 PUFAs might be stronger in participants with specific clinical
diagnoses than in those without specific clinical conditions. Larger and well-designed clinical trials
should be performed with high-dose omega-3 PUFAs, provided as monotherapy and as adjunctive
treatment to standard therapy.

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ARTICLE INFORMATION
Accepted for Publication: July 5, 2018.
Published: September 14, 2018. doi:10.1001/jamanetworkopen.2018.2327
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2018 Su K-P et al.
JAMA Network Open.
Corresponding Author: Yutaka J. Matsuoka, MD, PhD, Division of Health Care Research, Center for Public Health
Sciences, National Cancer Center Japan, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan (yumatsuo@ncc.go.jp);
Kuan-Pin Su, MD, PhD, China Medical University Hospital, No. 2, Yude Road, North District, Taichung City, Taiwan
404 (cobolsu@gmail.com).
Author Affiliations: Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan (Su); Mind-
Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan (Su); College of
Medicine, China Medical University, Taichung, Taiwan (Su, Matsuoka); WinShine Clinics in Specialty of Psychiatry,
Kaohsiung City, Taiwan (Tseng); Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung,
Taiwan (Lin); Chang Gung University College of Medicine, Kaohsiung, Taiwan (Lin); Institute for Translational
Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (Lin); Division of
Health Care Research, Center for Public Health Sciences, National Cancer Center Japan, Tokyo, Japan (Okubo,
Matsuoka); Department of Psychiatry, Tri-Service General Hospital, Taipei, Taiwan (T.-Y. Chen); School of Medicine,
National Defense Medical Center, Taipei, Taiwan (T.-Y. Chen); Institute of Brain Science, National Yang-Ming
University, Taipei, Taiwan (T.-Y. Chen); Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung, Taiwan
(Y.-W. Chen).
Author Contributions: Dr Tseng had full access to all of the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data analysis. Drs Su and Tseng contributed equally.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data: Su, Tseng, Okubo, Matsuoka.
Drafting of the manuscript: Su, Tseng, Okubo, Y.-W. Chen, Matsuoka.
Critical revision of the manuscript for important intellectual content: Su, Tseng, Lin, Okubo, T.-Y. Chen, Matsuoka.
Statistical analysis: Tseng, Lin, Y.-W. Chen.
Obtained funding: Su, Matsuoka.
Administrative, technical, or material support: Su, T.-Y. Chen.
Supervision: Su, Matsuoka.
Conflict of Interest Disclosures: Dr Su reported grants from the Ministry of Science and Technology, the National
Health Research Institutes, and the China Medical University during the conduct of the study. Dr Matsuoka
reported receiving donations from Morinaga Milk Industry Co, Ltd outside the submitted work. No other
disclosures were reported.
Funding/Support: The work was supported in part by grant 17H04253, Grant-in-Aid for Scientific Research (B)
from the Japan Society for the Promotion of Science; grant 30-A-17 from the National Cancer Center Research and
Development Fund; grants MOST106-2314-B-039-027-MY, 106-2314-B-038-049, 106-2314-B-039-031,
106-2314-B-039-035, 104-2314-B-039-022-MY2, and 104-2314-B-039-050-MY3 from the Ministry of Science
and Technology, Taiwan; grant HRI-EX105-10528NI from the National Health Research Institutes, Taiwan; and
grants CRS-106-063, DMR-107-202, and DMR-107-204 from the China Medical University, Taiwan.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; review or approval of the manuscript; and decision to
submit the manuscript for publication.

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SUPPLEMENT.
eAppendix. Excluded Studies and Reasons
eTable. Study Design and Jadad Scores of Recruited Studies
eFigure 1. Whole Flowchart of Current Meta-Analysis
eFigure 2. Funnel Plot of Changes in Anxiety Symptoms in Patients With and Without n-3 PUFA Treatment
eFigure 3. Subgroup MA of Anxiolytic Effect Based Upon Placebo Controlled or Non–Placebo Controlled Design

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